P ROTEASOME I NHIBITORS IN M ANTLE C ELL L YMPHOMA Owen A. OConnor, - - PowerPoint PPT Presentation

PROTEASOME INHIBITORS IN MANTLE CELL LYMPHOMA

Founding Director, Center for Lymphoid Malignancies Professor of Medicine and Developmental Therapeutics The New York Presbyterian Hospital Columbia University College of Physicians and Surgeons New York, N.Y.

Owen A. O’Connor, M.D., Ph.D.

2nd Post-Graduate Lymphoma Conference Rome, Italy March 23

PROTEASOME INHIBITORS IN MANTLE CELL LYMPHOMA

• Proteasome Inhibitors and the

Proteasome : A Gentle Reminder

• Mantle Cell Lymphoma
• Indolent Lymphomas
• Diffuse Large B-Cell Lymphoma
• Peripheral T-Cell Lymphoma
• Summary : Novel - Novel Prospects

PROTEASOME INHIBITORS IN LYMPHOMA

• Rationale

– Disrupts pathways involved in pathogenesis of lymphoma – Preclinical models show sensitivity of lymphoma cell lines to

proteasome inhibitors

O’Connor. Clin Lymphoma Myeloma. 2005;6:191; Leonard. Int J Cancer. 2006;119:971; Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; 2003; Demo. Cancer Res. 2007;67:6383; Ahn. Blood. 2007 [Epub ahead of print]; Stewart. ASCO 2007 (abstr 8003); Chauhan. Br J Cancer. 2006;95:961.

NPI-0052 Irreversible inhibitor Early phase I testing Bortezomib Reversible inhibitor Approved for MCL Carfilzomib (PR-171) Irreversible inhibitor Phase I testing

EFFECTS OF BORTEZOMIB ON TUMOR AND STROMAL TARGETS : PLEIOTROPIC DRUGS

• Kyle. N Engl J Med. 2004;351:1860; Adams. Drug Disc Today. 2003;8:307; Adams. Invest New Drugs.

2000;18:109; Voorhees. Clin Cancer Res. 2003;6:6316; Leonard. Int J Cancer. 2006;119:971; Richardson. Cancer

• Control. 2003;10:361; Ling. Mol Cancer Ther. 2002;1:841.

MAPK=mitogen-activated protein kinase; NF-B=nuclear factor kappa B.

Microenvironment ↓ NF-B, ↓ cytokines, ↓ cell adhesion molecules, ↓ VEGF, ↓ TNF-α Apoptosis ↑ p53, ↑ p21, ↑ Bax, ↑ tBID, ↑ Bcl-2, ↓ MAPK, ↓ survivin, ↓ XIAP, ↓ cIAP

↑ Caspases

Cell-Cycle Arrest ↑ p53, ↑ p21, ↑ p27, ↓ NF-B, ↓ MAPK, ↑ cyclins A/B/D/E, ↑ c-fos/c-jun, ↑ Myc, ↑ beta catenin Stress Response ↓ DNA repair, ↓ Pgp, ↑ TopII, ↑ TopI, ↓ NF-B, ↓ MAPK, chemo- and radiosensitization

NOVEL TARGETS/THERAPIES: PROTEASOME INHIBITORS

• Proteasome Inhibitors and the

Proteasome : A Gentle Reminder

• Mantle Cell Lymphoma
• Indolent Lymphomas
• Diffuse Large B-Cell Lymphoma
• Peripheral T-Cell Lymphoma
• Summary: Novel - Novel Prospects

SINGLE-AGENT ACTIVITY OF BORTEZOMIB IN MANTLE CELL LYMPHOMA

Study Bortezomib Regimen Evaluable Patients (n) CR/CRu PR OR O’Connor

(ICML 2005)

1.5 mg/m2 days 1, 4, 8, 11 21-day cycle 37 13% 27% 40% Goy

(JCO 2005)

1.5 mg/m2 days 1, 4, 8, 11 21-day cycle 29 21% 21% 41% Strauss/Lister

(IMCL 2005)

1.3 mg/m2 days 1, 4, 8, 11 21-day cycle 24 4% 25% 29%

Belch

(ASH 2004)

1.3 mg/m2 days 1, 4, 8, 11 21-day cycle 13 untreated 15 treated 0% 7% 46% 40% 46% 47%

PINNACLE (ASCO 2005)

1.3 mg/m2 days 1, 4, 8, 11 21-day cycle 141 8% 26% 33%

Bortezomib in Relapsed / Refractory MCL

Dose n ORR CRR Fisher JCO 2006 Goy Ann Onc 2009 1.3 BIW 141 31% 8%

LYM-3002: PHASE III RANDOMIZED, OPEN-LABEL, MULTI-CENTER TRIAL OF R-CHOP VS. VCR-CAP IN PREVIOUSLY UNTREATED MCL INELIGIBLE FOR SCT

Cavalli F et al. ASCO 2014, abstract #8500

VcR-CAP

Rituximab 375 mg/m2 IV d 1 Cyclophosphamide 750 mg/m2 IV d 1 Doxorubicin 50 mg/m2 IV d 1 Prednisone 100 mg/m2 PO d 1–5 Vincristine 1.4 mg/m2 (max. 2 mg) IV d 1

R-CHOP

Randomization 1:1 stratified by: IPI score (0–1, 2, 3, 4–5) Disease stage at diagnosis (II, III, IV) Newly diagnosed MCL patients: Measurable stage II–IV MCL ECOG PS 0–2 Ineligible or not considered for BMT 6–8 x 21-day cycles (up to 8 cycles if investigator-assessed response first documented at cycle 6) Rituximab 375 mg/m2 IV d 1 Cyclophosphamide 750 mg/m2 IV d 1 Doxorubicin 50 mg/m2 IV d 1 Prednisone 100 mg/m2 PO d 1–5 Bortezomib 1.3 mg/m2 IV d 1, 4, 8, 11

Response-evaluable population R-CHOP (n=244) VcR-CAP (n=243) HR P CR+CRu*, % 42 53 OR 1.69 0.007 ORR (CR+CRu+PR), % 90 92 OR 1.43 0.275 Median time to initial response, mos 1.6 1.4 HR 1.54 <0.001 Median DOR (CR+CRu+PR), mos 15.1 36.5 NA NA In patients with CR+CRu* 18.5 42.1 NA NA Median duration of CR/CRu, mos 18.0 42.1 NA NA Median TTP by IRC, mos 16.1 30.5 HR 0.58 <0.001 By investigator, mos 16.8 35.0 HR 0.47 <0.001 Median time to next therapy (TTNT), mos 24.8 44.5 HR 0.50 <0.001 Median treatment-free interval (TFI), mos 20.5 40.6 HR 0.50 <0.001 Median OS, mos 56.3 NR HR 0.80 0.173 4-year OS rate, % 53.9 64.4 – –

LYM-3002: PHASE III RANDOMIZED, OPEN-LABEL, MULTI- CENTER TRIAL OF R-CHOP VS. VCR-CAP IN PREVIOUSLY UNTREATED MCL INELIGIBLE FOR SCT

Secondary outcomes: Response and DOR by IRC, TTP, TTNT, TFI, OS

Cavalli F et al. ASCO 2014, abstract #8500

*CR/CRu verified by bone marrow and LDH; † data shown are odds ratio (OR), except for hazard ratio (HR) for time to response; NA, not applicable; NR: not reached

59% improvement in PFS by IRC with VcR-CAP vs R-CHOP (median follow-up 40 mos)

Cavalli F et al. ASCO 2014, abstract #8500

LYM-3002: PHASE III RANDOMIZED, OPEN-LABEL, MULTI- CENTER TRIAL OF R-CHOP VS. VCR-CAP IN PREVIOUSLY UNTREATED MCL INELIGIBLE FOR SCT

R-CHOP VcR-CAP Events, n 165 133 Median PFS, months 14.4 24.7 (95% CI) (12.0, 16.9) (19.8, 31.8) HR (95% CI) 0.63 (0.50, 0.79) P-value <0.001

Patients alive and progression-free, % 100 80 60 40 20 6 12 18 24 30 36 42 48 54 60 66 Months from randomization

R-CHOP VcR-CAP

Number of patients at risk: R-CHOP 244 181 116 79 55 36 22 16 9 3 VcR-CAP 243 187 146 122 94 66 42 28 17 8 1

Median PFS by investigator was 16.1 vs 30.7 mos with R-CHOP vs VcR-CAP; 307 (63%) events; HR 0.51, p<0.001; 96% improvement with VcR-CAP

At Cost of More Toxicity : Neuropathy

LYM-3002: PHASE III RANDOMIZED, OPEN-LABEL, MULTI- CENTER TRIAL OF R-CHOP VS. VCR-CAP IN PREVIOUSLY UNTREATED MCL INELIGIBLE FOR SCT

Secondary outcomes: OS (Median follow-up 40 mos)

Cavalli F et al. ASCO 2014, abstract #8500

There was a trend to prolonged survival with VcR-CAP (not statistically significant)

Patients alive, % 100 6 12 18 24 30 36 42 48 54 60 66 72 Months from randomization R-CHOP VcR-CAP 80 60 40 20

Number of patients at risk: R-CHOP 244 214 204 192 177 141 100 70 43 21 7 1 VcR-CAP 243 212 200 191 171 140 100 75 52 28 8 1

R-CHOP VcR-CAP Events, n 87 71 Median OS, months 56.3 Not reached (95% CI) (47.2, NE) (56.0, NE) HR (95% CI) 0.80 (0.59, 1.10) P-value 0.173

E1411 - Phase 2 Intergroup Trial: Initial Therapy of Mantle Cell Lymphoma in patients  age 60

R E G I S T R A T I O N

BR x 6 BVR x 6 Lenalidomide + Rituximab

BR = Bendamustine, Rituximab V= Bortezomib

Randomized phase II, N ~ 328; 82 eligible per arm

BR x 6 BVR x 6 Lenalidomide + Rituximab Rituximab Rituximab

BBR (VERTICAL) ; ORR 88%, complete response rate 53%, median PFS 15 mos

(Fowler, et al, JCO 2011)

PROTEASOME INHIBITORS IN MANTLE CELL LYMPHOMA: SUMMARY OF CLINICAL STATUS

• In lymphoma, MCL remains the only US FDA

approval for the drug

• Most use now has matured to combination use in

R-CHOP and R-Bendamustine, though ECOG results are pending

• Activity appreciated in MZL, PTCL, perhaps sub-

types of DLBCL

• Novel : novel combinations are proving

interesting……

HOW DO WE IMPROVE THE MERITS OF PROTEASOME INHIBITORS? Make Better Ones Or Identify Synergistic Combinations (not predicated on genotoxic chemtherapy)

IXAZOMIB (MLN2238)

• First orally bioavailable

proteasome inhibitor in clinical trials

• Binds to the chymotrypsin-

like site of the 20S proteasome

• Similar selectivity and

potency to bortezomib, but shorter 20S proteasome dissociation half-life

PHASE 1 STUDY OF IV IXAZOMIB IN LYMPHOMA

• IV administration on days 1, 8, 15 of 28 days
• 30 subjects with relapsed/refractory NHL

– FL 11, DLBCL 5, PTCL 4, HL 3, MF 2, MCL 2, Other 2

• MTD determined to be 2.34 mg/m2
• DLTs: Neutropenia, diarrhea, renal failure
• Most common AEs: fatigue (43%), diarrhea (33%),

nausea, thrombocytopenia, rash (each 27%)

• 26 evaluable for response, 5 responders (19%)

– 1 CR (FL), 4 PRs (3 FL, 1 PTCL)

Assouline et al. Blood Can J 2014

Carfilzomib

• Tetrapeptide ketoepoxide-based irreversible inhibitor of

the 20S proteasome.

• Higher affinity for proteasome than bortezomib, and

demonstrated activity in bortezomib resistant NHL cell lines

• Phase 1 trial reached 20/27 mg/m2 on days 1,2, 8, 9, 15,

16 of a 28 day cycle. No MTD reached.

• Anemia, thrombocytopenia, nausea, fatigue, constipation,

pyrexia, cough, anorexia

• Among 15 NHL, 5 SD (4 FL, 1 CLL/SLL)

Ou, et al, AACR abstract #2432, 2013 The bruton’s tyrosine kinase inhibitor ibrutinib synergized with the proteasome inhibitor carfilzomib and overcame immunoproteasome- mediated carfilzomib resistance in mantle cell lymphoma Dasmahapatra et al, Br J Haematol 2013 Combinatorial drug screening identifies synergistic co- targeting of Bruton’s Tyrosine Kinase and the proteasome in Mantle Cell Lymphoma

Axelrod, Ou, Brett et al, Leukemia 2013 Proteasome Inhibitors Synergize with BTK Targeted Drugs

TARGETING TRANSLATION WITH PROTEASOME AND PI3K INHIBITORS BY INHIBITING PHOSPHORYLATION OF 4E-BP1

Dibble CC and Cantley LC. Trends Cell Biol, 2015 Andresen et al., Nucleic Acids Res 2012 Wolfe et al., Nature 2014 Suraweera, A., et al., Mol Cell, 2012 Quy, P.N., et al., J Biol Chem, 2013 Hutter, G., et al., Leukemia, 2012 Zhang, Y., et al., Nature, 2014

c-Myc [Cyclin D1 Bcl2] eIF4E 4E-BP1 eIF4E eIF4A eIF4G P P 4E-BP1 (eIF4F)

Translation

mTOR PI3Kd Proteasome Amino acids AKT ?Other? Kinases

COMBINING PI3K AND PROTEASOME INHIBITORS SYNERGISTICALLY INHIBITS TRANSLATION OF C-MYC WITH POTENT CYTOTOXICITY: EXPERIMENTAL DESIGN

Drugs TGR-1202 (TG) Idelalisib (Ide) Carfilzomib (Cfz) TC IC Bortezomib (Bz) TB IB

x x

eIF4F c-Myc mTORC1 PI3K Proteasome pp-4E-BP1

PI3Kδ Inhibitors Proteasome Inhibitors

x

Deng et al., 2017. Blood

CAL-101 (uM) Carfilzomib (uM) Bortezomib (uM) TGR-1202 (uM)

EOB: > 0 to 100: Synergy

HIGHLY SYNERGISTIC INTERACTIONS UNIQUE TO THE CAR - TGR1202 COMBINATION

Deng et al., 2017. Blood

20 40 60 80 100 120 1,25 2,5 5

Cell Viability Concentration (nM)

Jeko-1-48 hrs

Cfz 2.5uM TGR-1202+Cfz 5uM TGR-1202+Cfz 10uM TGR-1202+Cfz 15uM TGR-1202+Cfz 20 40 60 80 100 120 1,25 2,5 5

Cell Viability Concentration(nM)

Rec-1_48 hrs

Cfz 2.5uM TGR-1202+cfz 5uM TGR-1202+Cfz 10uM TGR-1202+Cfz 15uM TGR-1202+Cfz 20 40 60 80 100 120 1,25 2,5 5

Cell Viability Concentration (nM)

JVM-2_48 hrs

Cfz 2.5uM TGR-1202+Cfz 5uM TGR-1202+Cfz 10uM TGR-1202+Cfz 15uM TGR-1202+Cfz 20 40 60 80 100 120 1,25 2,5 5

Cell Viability Concentration(nM)

Z-138_48 hrs

Cfz 2.5uM TGR-1202+Cfz 5uM TGR-1202+Cfz 10uM TGR-1202+Cfz 15uM TGR-1202+Cfz

Carfilzomib(nM) 1.25 2.5 5 Jeko-1 2.5 7.18 20.06 27.44 5 9.75 25.52 39.46 10

• 0.61

9.23 26.02 Rec-1 2.5

• 12.4

4.44 40.56 5

• 9.56 22.99 67.6

10

• 13.1 -6.92 40.31

Z-138 2.5

• 2.86
• 0.6 17.9

5

• 2.12 10.66 30.62

10

• 6.93 24.96 35.98

JVM-2 2.5 7.41 12.1 -0.74 5 4.93 14.7 2.21 10 5.12 13.09 9.95

TC IS SYNERGISTIC AND SUPERIOR TO COMPARATORS IN CLEAVING PARP AND ELIMINATING C-MYC AND CYCLIN D1 IN MANTLE CELL LYMPHOMA

TGR-1202(µM) CK1Є c-Myc CyclinD1 β-actin PARP β-actin Jeko-1 12 hrs 24 hrs 24 hrs 24 hrs

TC IS HIGHLY SYNERGISTIC AND SUPERIOR

TO OTHER COMBINATIONS

SUMMARY OF FINDINGS

• TC is highly synergistic in 12 cell line models of DLBCL, MM,

T-ALL, CTCL and Mantle Cell Lymphoma

• In MCL the combination eliminates c-myc and Cyclin D1
• TC is highly synergistic in primary CLL, MCL, and MZL cells.
• TC synergistically induces apoptosis.

Deng et al., Blood 2017

TC UNIQUELY AND SYNERGISTICALLY INHIBITS TRANSLATION

OF C-MYC AND PHOSPHORYLATION OF 4E-BP1

LY10

4EBP1*T70 4EBP1 c-Myc Actin

LY7

4EBP1*T70 c-Myc B-Actin 4EBP1

SLL CLL

Additionally…..

• TC does not inhibit the mRNA level of c-Myc.
• A reporter of MYC 5’UTR confirms TC inhibits translation of c-Myc.

Deng et al., Blood 2017

Running Enrichment Score (RES) GS52: Schuhmacher Gene List Index NES q-val

• 7.70 0.00

Gene List Index GS70: Dang RES NES q-val

• 6.56 0.00

TC INHIBITS THE TRANSCRIPTION OF C-MYC TARGET GENES : GSEA CONFIRMS C-MYC AS TARGET

Additionally…

• Cytotoxicity of TC is rescued by forced overexpression of c-Myc.
• Cytotoxicity of TC is rescued by forced overexpression of eIF4E.

Deng et al., Blood 2017

TGR-1202 and carfilzomib, but not combinations of other drugs in the same class, synergistically inhibit c-Myc translation and c-Myc dependent gene transcription, by potently inhibiting phosphorylation of 4E-BP1. TGR-1202 and carfilzomib synergistically induce apoptosis In lymphoma cells through targeting c-Myc.

Deng et al., Blood 2017

But, what accounts for the differences between the PI3 kinase inhibitors?

Idelalisib Duvelisib TGR-1202

TGR-1202 IS STRUCTURALLY DISTINCT FROM IDELALISIB

AND DUVELISIB

Kinase #1 #2 #1 #2 #1 #2 CK1a1 111 111 110 107 112 111 CK1a1L 105 103 102 101 104 99 CK1delta 105 98 96 104 100 97 CK1epsilon 40 40 93 93 93 91 CK1g1 99 98 105 105 102 98 CK1g2 104 104 102 100 99 99 CK1g3 96 95 94 93 93 93 CK2a 83 78 97 96 95 84 CK2a2 86 86 94 92 102 100

TGR-1202, BUT NOT IDELALISIB OR DUVELISIB, INHIBITS CASEIN KINASE 1 EPSILON (CK1Ε)

Kinase activity (% of control) using the Reaction Biology Kinome Profiling (i.e. functional) platform

TGR-1202 Idelalisib Duvelisib

L85 E83 L84 L135 M82 S88

PF4800567 (X-Ray) TGR-1202 (In silico docking)

TGR-1202 AND THE CK1E INHIBITOR PF4800567 SHARE AN IDENTICAL STRUCTURAL MOIETY

N N N N NH

2

O Cl O

3 1 2 4 5 6 7 8 9

Central pyrazolo- pyrimidine moiety PF4800567

N N N N NH

2

O F O O F F

TGR-1202

3 1 2 4 5 6 7 8 9

eIF4F c-Myc & Others

Translation

mTOR PI3Kd Proteasome pp-4EBP1 TGR-1202 Carfilzomib, Bortezomib CK1 Idelalisib

TGR-1202 AS THE FIRST CK1Ε INHIBITOR AVAILABLE FOR PATIENTS MAY HAVE A UNIQUE THERAPEUTIC ROLE IN C-MYC /CYCLIN D1 DRIVEN LYMPHOMA WITH PROTEASOME INHIBITORS NCT02867618: actively enrolling patients Phase I/II Study of TGR-1202 and Carfilzomib in the Treatment

• f Patients with Relapsed or Refractory Lymphoma

NOVEL TARGETS/THERAPIES: PROTEASOME INHIBITORS

• 20 years later, we have much to learn about how these

drugs work

• These drugs are pleiotropic drugs, MOA may be very cell

context specific (i.e, MCL-1, NOXA, etc.) but others exist too

• Proteasome inhibitors are the prototypical companion drug;

they synergize with almost everything…..

• Espicially ….targeting the proteasome with unique PI3K

inhibitors could emerge as a novel c-myc targeted strategy

CENTER FOR LYMPHOID MALIGNANCIES AT COLUMBIA UNIVERSITY MEDICAL CENTER

Physicians Owen A. O’Connor, M.D., Ph.D. Jennifer Amengual, M.D. Changchun Deng, M.D., Ph.D. Ahmed Sawas, M.D. Donald Colburn, M.D. Nurses/Clinical Staff Michael Smith, RN Emily Lichtenstein, RN Karen Khan, RN Heather Dials, NP Joanne Scibilla, MT Laboratory Staff LLuigi Scotto, Ph.D. Michael Mangone, Ph.D. Jennifer Amengual, M.D. Changchun Deng, M.D., Ph.D. Yuxuan Liu, Ph.D. Xavier Jirau Serrano, B.S. Mark Lipstein, B.S. Sathyen Praehu, M.D. Yulissa Gonzalez, B.S. Cristina, Kinahan, M.S Administrative Staff Victoria Serrano, MPH Carolyn Baldwin, MPH Erica Guererva, B.S. Heather Laut, B.S. Joanna Duarte, B.S. Research Study Coordinators Ithamar, Turenne, B.S. Aisha Banks, B.S. Celeste Rojas, B.S. Renee Lichtenstein, B.A Michele Malanga, BA Fellows Matko Kalac, M.D., Ph.D Jennifer Lue, M.D. Enrica Marchi, M.D., Ph.D. Lorenzo Falchi, M.D.

Thank You!

(LY10 DLBCL)

HIF1a c-Myc BCL-2 eIF4E eIF4A eIF4G B-Actin B-Actin

mTOR Cap dependent translation Transcription c-Myc

TARGETING THE EIF4E COMPLEX AS A MEANS TO ‘TURN-OFF’ C-MYC

3 3 5 5 5 5 5 5

• +
• +
• +

shRNA Ide (mM) Cfz (nM) B-Actin CK1 4EBP1 4EBP1 *T70 c-Myc 4EBP1 *S65 4EBP1 *T70 4EBP1 B-Actin

DUAL TARGETING OF PI3KΔ AND CK1Ε UNDERSCORES THE UNIQUE ACTIVITY OF TGR-1202 IN DLBCL

CAL-101 (uM) TGR-1202 (uM) Carfilzomib (uM) Bortezomib (uM) (2A)

CARFILZOMIB AND TGR-1202 DEMONSTRATES HIGHEST SYNERGY

(LY10 DLBCL) P-Akt S473 Raptor B-Actin P-4EBP1 4EBP1 B-Actin P-STAT3 STAT3 P-S6K B-Actin

PI3K Phos-AKT

P-T308

mTOR Raptor mTORC1 TSC 1/2 mTOR Rictor mTORC2

P-S473 P-S2481

4EBP1 STAT3 p70S6K P P P

THE COMBINATION OF CAR – TGR-21202 UNIQUE TURNS OFF P4EBP1

NOVEL TARGETS/THERAPIES: PROTEASOME INHIBITORS

• Proteasome Inhibitors and the

Proteasome : A Gentle Reminder

• Mantle Cell Lymphoma
• Indolent Lymphomas
• Diffuse Large B-Cell Lymphoma
• Peripheral T-Cell Lymphoma
• Summary: Novel - Novel Prospects

BORTEZOMIB IN RELAPSED/REFRACTORY DLBCL

Dunleavy et al. Blood 2009.

ORR CRR All 42% 23% ABC 83% 42% GCB 13% 7%

BORTEZOMIB PLUS DA-EPOCH-R IN RELAPSED DLBCL

Dunleavy et al. Blood 2009.

OS 8 mo 11 mo 3 mo

BENEFIT OF BORTEZOMIB IN FRONT-LINE?

R-CHOP

Meyer, et al. JCO 2010 Ruan et al. JCO 2011

R-CHOP-bortezomib

Await results from randomized trials: PYRAMID, LYM2034, REMoDLB

RANDOMIZED PHASE 2 OPEN LABEL STUDY OF R- CHOP +/- BORTEZOMIB IN PATIENTS WITH UNTREATED NON-GCB DLBCL: RESULTS FROM THE PYRAMID TRIAL

• Non-GCB DLBCL measurable disease confirmed

by Hans.

• R-CHOP vs VR-CHOP (Bortezomib 1.3 mg/m2

Day 1 & 4)

• Primary ednpoint : PFS
• 206 patients randomized at 69 sites; 183 had

centrally confirmed non-GCB DLBCL)

• 86% and 85% of patients complete study per

treatment

Parameter R-CHOP VR-CHOP HR ORR/CR 98/52 92/54 2-Y PFS 77% 82% 0.77; p=0.7 HI/H IPI 2-Y PFS 64% 72% 0.66; p = 0.3 Died 15% 11% 0.65 HI/H-2 Y OS 79 92 2-Y-OS L/LI 98% 98%

Conclusion: No significant efficacy advantage with theaddition of R- CHOP in patients with previously untreated non-GCB DLBCL

RANDOMIZED PHASE 2 OPEN LABEL STUDY OF R-CHOP +/- BORTEZOMIB IN PATIENTS WITH UNTREATED NON-GCB DLBCL: RESULTS FROM THE PYRAMID TRIAL

NOVEL TARGETS/THERAPIES: PROTEASOME INHIBITORS

• Proteasome Inhibitors and the

Proteasome : A Gentle Reminder

• Mantle Cell Lymphoma
• Indolent Lymphomas
• Diffuse Large B-Cell Lymphoma
• Peripheral T-Cell Lymphoma
• Summary: Novel - Novel Prospects

For the T-Cell Enthusiasts

• N=12

– 10 Mycosis Fungoides, – 2 PTCLu

• ORR 67%
• CR Rate 17%

Zinzani et al. JCO 2007

Study Schema of SGH 651

• Primary endpoint: Objective Response Rate (ORR)
• Secondary endpoints: Time-to-response, duration of

response, PFS, OS, safety and tolerability

Patients (N = 25) Relapsed/refractory PTCL

(subtypes: PTCL-NOS, AITL, NK/T-cell lymphoma, EATL, hepatosplenic T-cell lymphoma, ALK- ALCL, or ALK+ ALCL with post-ASCT relapse)

At least 1 line of prior systemic therapy Panobinostat + Bortezomib (21-day cycles) Continue for 8 cycles

OR

Transplant if suitable candidate

8-weekly CT-scans (or PET-CT scans)

SGH protocol 651 PHASE II, MULTI-NATIONAL, OPEN LABEL, SINGLE-ARM, INVESTIGATOR-INITIATED STUDY (NCT00901147).

PRIMARY ENDPOINT: OBJECTIVE RESPONSE RATE

Response N=23 (%) ORR

10 (43)

CR

5 (22)

PR

5 (22)

SD

5 (22)

PD

8 (35) Histological Subtypes

PTCL-NOS 2/9 (22) Angioimmunoblastic T-cell lymphoma 4/8 (50) ALK+ Anaplastic large cell lymphoma 1/1 (100) ALK- Anaplastic large cell lymphoma 1/4 (25) NK/T-cell lymphoma, nasal type 1/2 (50) Subcutaneous panniculitis-like T-cell lymphoma 1/1 (100)

SGH protocol 651

WATERFALL PLOT TIME-TO-RESPONSE & DURATION OF RESPONSE

• Median time to

response : 6 weeks (range 5 – 18)

• Median

duration of response : 5.6 months (range 2 – 33)

• 100
• 75
• 50
• 25

25 50 75 100

SPD of measured lymph nodes (Best ORR % change from baseline)

Patients (N = 23)

SGH protocol 651

NOVEL TARGETS/THERAPIES: PROTEASOME INHIBITORS

• Proteasome Inhibitors and the

Proteasome : A Gentle Reminder

• Mantle Cell Lymphoma
• Indolent Lymphomas
• Diffuse Large B-Cell Lymphoma
• Peripheral T-Cell Lymphoma
• Summary: Novel - Novel Prospects

ONGOING STUDIES WITH ADDITIONAL NOVEL AGENTS

• Bortezomib and Lenalidomide in Treating Patients With Relapsed or

Refractory Mantle Cell Lymphoma

• Phase I/II Carfilzomib Plus Lenalidomide and Rituximab in the Treatment of

Relapsed/Refractory Mantle Cell Lymphoma

• Bortezomib + obatoclax in MCL
• Ibrutinib in Combination With Carfilzomib in Relapse/Refractory Mantle Cell

Lymphoma

• Bortezomib and Azacitidine in Relapsed or Refractory T-Cell Lymphoma
• Everolimus and Bortezomib in Relapsed or Refractory Lymphoma
• Ibrutinib and Bortezomib to Treat Patients With Mantle Cell Lymphoma
• Alisertib, Bortezomib, and Rituximab in Relapsed or Refractory Mantle Cell

Lymphoma or B-cell Low Grade Non-Hodgkin Lymphoma

PHASE II COMBINATIONS IN MCL

Dose n ORR CRR PFS Previously treated BBR Friedberg et al Blood 2011 30 (7 MCL) 83% 52% 3y 47% Initial Therapy VcR-CVAD + maint R Chang et al Blood 2014 75 95% 68% 3y 68% RiBVD Gressin et al Proc ASH 2014 74 nr 74% 2y 69%

• Pts received a median of 6 cycles (1-8) in each arm
• 83% in R-CHOP arm and 84% in VcR-CAP arm received ≥6 cycles

AE, % (safety population) R-CHOP (n=242) VcR-CAP (n=240) All-grade AE 98 99 Drug-related all-grade AE 93 96 Grade ≥3 AE 85 93 Drug-related grade ≥3 AE 80 91 Serious AE 30 38 Drug-related serious AE 21 33 AE leading to discontinuation 7 9 Drug-related AE leading to discontinuation 6 8 On-study deaths (within 30 days of last dose) 6 5 Deaths due to drug-related AE 3 2

LYM-3002: PHASE III RANDOMIZED, OPEN-LABEL, MULTI-CENTER TRIAL OF R-CHOP VS. VCR-CAP IN PREVIOUSLY UNTREATED MCL INELIGIBLE FOR SCT

Overall safety profile

Cavalli F et al. ASCO 2014, abstract #8500

AE, % (safety population) R-CHOP (n=242) VcR-CAP (n=240) At least one grade ≥3 AE 85 93 Neutropenia 67 85 Leukopenia 29 44 Thrombocytopenia 6 57 Lymphopenia 9 28 Anemia 14 15 Febrile neutropenia 14 15 Pneumonia 5 7 Fatigue 3 6 Peripheral sensory neuropathy 3 5 Diarrhea 2 5 At least one SAE 30 38 Febrile neutropenia 8 11 Pneumonia 3 8 Neutropenia 5 5

LYM-3002: PHASE III RANDOMIZED, OPEN-LABEL, MULTI-CENTER TRIAL OF R-CHOP VS. VCR-CAP IN PREVIOUSLY UNTREATED MCL INELIGIBLE FOR SCT

Grade ≥3 AE and SAE (≥5% in either arm)

Cavalli F et al. ASCO 2014, abstract #8500

• Grade ≥3 bleeding events: 1.2% R-CHOP vs 1.7% VcR-CAP
• Grade ≥3 infections: 14% R-CHOP vs 21% VcR-CAP

VR-CAP versus R-CHOP as initial therapy

Robak et al NEJM 2015

n ORR CRR R-CHOP 244 89% 42% VR-CAP 243 92% 53%

R-CHOP (n=242) VcR-CAP (n=240) Peripheral neuropathy*, % 29 30 Grade ≥3 peripheral neuropathy, % 4.1 7.5 Treatment discontinuations, % <1 2 Median time to onset, days (range) 52 (2–158) 83 (8–256) Events improved/resolved, % 79 90 Events resolved, % 75 81 Median time to improvement/resolution, months (95% CI) 4.8 (2.8, 6.4) 1.5 (0.9, 2.0) Median time to resolution, months (95% CI) 5.5 (3.9, 8.1) 3.0 (1.6, 4.7)

LYM-3002: PHASE III RANDOMIZED, OPEN-LABEL, MULTI- CENTER TRIAL OF R-CHOP VS. VCR-CAP IN PREVIOUSLY UNTREATED MCL INELIGIBLE FOR SCT

Peripheral neuropathy NEC*

Cavalli F et al. ASCO 2014, abstract #8500

*Peripheral neuropathy NEC, high-level term including peripheral sensory neuropathy, neuropathy

peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy

ITT population R-CHOP (N=244) VcR-CAP (N=243) Age Median, yrs (range) >60 yrs, % (range) >65 yrs, % (range) 66 (34-82) 73 55 65 (26-88) 73 53 ECOG PS, % 1 2 35 52 13 46 42 13 IPI score, % 0-1 2 3 4-5 16 29 36 19 16 31 35 19 Disease stage at diagnosis, % II III IV 7 20 74 6 20 75

LYM-3002: PHASE III RANDOMIZED, OPEN-LABEL, MULTI-CENTER TRIAL OF R- CHOP VS. VCR-CAP IN PREVIOUSLY UNTREATED MCL INELIGIBLE FOR SCT

• Endpoints: Primary: PFS as measured by an independent radiology review committee

(IRC). Secondary: response by modified IWG criteria1 [ORR (CR+CRu+PR) and complete response (CR+CRu), TTR, DOR, duration of CR+CRu, TTP, TTNT, TFI, OS, and AE

• Patients: 487 pts with previously untreated, measurable stage II-IV MCL, ECOG PS 0-

2, ineligible or non considered for SCT

Cavalli F et al. ASCO 2014, abstract #8500

• 1. Cheson et al. JCO 2007

SUBSET-DIRECTED THERAPY IN ABC-DLBCL

Modified from Yang et al. Cancer Cell 2012

Ibrutinib Bortezomib